CN107474011A - A kind of the stibazole class LSD1 inhibitor of 2 phenyl 4, its preparation method and application - Google Patents

A kind of the stibazole class LSD1 inhibitor of 2 phenyl 4, its preparation method and application Download PDF

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CN107474011A
CN107474011A CN201710750072.1A CN201710750072A CN107474011A CN 107474011 A CN107474011 A CN 107474011A CN 201710750072 A CN201710750072 A CN 201710750072A CN 107474011 A CN107474011 A CN 107474011A
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lsd1
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CN107474011B (en
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段迎超
关圆圆
刘兆敏
翟晓雨
秦文平
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Xinxiang Medical University
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

The invention discloses a kind of LSD1 inhibitor, its preparation method and application in antineoplastic is prepared with the stibazole structure of 2 phenyl 4, belong to field of pharmaceutical chemistry technology.Compound of the present invention has below formula：

Description

A kind of 2- phenyl -4- stibazole class LSD1 inhibitor, its preparation method and Using
Technical field
Present invention relates particularly to a kind of LSD1 inhibitor with 2- phenyl -4- stibazole structures, its preparation side Method and the application in antineoplastic is prepared, belong to field of pharmaceutical chemistry technology.
Background technology
Istone lysine specificity demethylase 1 (Lysine specific histone demethylase 1, LSD1) it is first histone demethylase being reported.LSD1 belongs to the amine of flavin adenine dinucleotide (FAD) (FAD) dependence Oxidizing ferment superfamily, LSD1 can be with specific removal istone lysine H3K4 and H3K9 single, double methyl.LSD1 may be used also To act on nonhistones substrate, for example LSD1 can remove the methyl in cancer suppressor protein p53K370 sites, suppress p53 target genes Expression；LSD1 can also make dnmt rna (DNMT1) demethylation, so as to maintain DNA overall methylation level. The generation of a variety of diseases such as LSD1 and tumour, viral infection, metabolic disease, inflammation has close relation, wherein with swelling The occurrence and development of knurl are particularly close.
LSD1 is in breast cancer, carcinoma of urinary bladder, acute myeloblastic leukemia, the cancer of the esophagus, stomach cancer, retinoblastoma, ovary Expression quantity in the kinds of tumors such as cancer significantly raises, and is proportionate with processes such as the growths, transfer and invasion and attack of these tumours.With RNA perturbation techniques reduce LSD1 expression quantity or can reduce related carcinogenophore with micromolecular inhibitor suppression LSD1 activity The expression of cause, suppress propagation, transfer and the invasion and attack of tumour.Therefore, LSD1 has become current tumour epigenetics treatment One of focus target, numerous international pharmaceuticals such as Spain Oryzon, the military field pharmacy of GlaxoSmithKline PLC and Japan are attracted Concern.Existing multiple LSD1 micromolecular inhibitors are reported at present, the tranylcypromine class LSD1 of Oryzon companies of Spain report Inhibitor currently carries out II clinical trial phases, for treating leukaemia.
Thus, it is found that new, high activity LSD1 micromolecular inhibitors, biological function, research and development for studying LSD1 The medicine of a variety of diseases especially tumour is of great significance.In order to find new LSD1 micromolecular inhibitors, The present invention has synthesized a kind of 2- phenyl -4- styrylpyridinium compounds, and such compound has significant LSD1 inhibitory activity And anti tumor activity in vitro, have not yet to see the report of the synthesis of such compound, LSD1 inhibitory activity and antitumor activity.
The content of the invention
From the foregoing, it is an object of the present invention to provide a kind of 2- phenyl -4- styryl pyridine compounds, Possibility is provided for novel drugs screening.
It is another object of the present invention to provide the preparation method of such 2- phenyl -4- styryl pyridine compounds And its application as istone lysine specificity demethylase 1 (LSD1) inhibitor.
Using LSD1 it is target spot in antineoplastic is prepared it is yet a further object of the present invention to provide the compound Using.
To achieve the above object, the general structure of 2- phenyl -4- styryl pyridine compounds involved in the present invention For：
In formula I, R1To be monosubstituted or polysubstituted, substituent refers to：NH2、In any one； R2For H, OH, Any one in CN, F, Cl, Br, I；R3For any one in H, OH, CN, F, Cl, Br, I.
It is preferred that：In formula I, R1To be monosubstituted, substituent refers to：NH2、In any one； R2For H, F, Cl, Any one in Br, I；R3For any one in H, F, Cl, Br, I.
It is highly preferred that R1、R2、R3The substituent and the position of substitution of representative are as shown in the table：
To realize above-mentioned second purpose, the synthetic reaction flow of the compounds of this invention is shown below：
The synthetic route of compound of Formula I：
R4For nitro or cyano group, R1, R2, R3Ibid.
The preparation method of compound 1:Substitute 2- methoxyphenylboronic acids and 2- bromopyridine -4- formaldehyde in toluene, alkalization In the presence of compound and palladium catalyst, return stirring reaction, compound 1 is obtained.Wherein, the alkali compounds is selected from potassium carbonate, carbon One kind in sour sodium, cesium carbonate, potassium phosphate, described palladium catalyst select tetrakis triphenylphosphine palladium, palladium, double (dibenzylidenes Acetone) palladium, one kind in palladium chloride.
The preparation method of compound 2:In DMF, strongly alkaline compound is present for compound 1 and substituted benzyl diethyl phosphonate Under, reaction is stirred at room temperature, after reaction terminates, reaction system is poured into frozen water, filters, washing, collects solid, dries, must change Compound 2.Wherein, the one kind of the strongly alkaline compound in potassium tert-butoxide, sodium methoxide, sodium hydride, sodium tert-butoxide.
The preparation method of compound 3:As R in compound 24For nitro, then in organic solvent, SnCl2In the presence of, backflow Stirring reaction, after reaction terminates, reaction system is concentrated in vacuo, and concentrate adds ethyl acetate, saturated sodium bicarbonate aqueous solution stirs Mix, divide and take organic phase, wash, dry, column chromatography for separation, obtain compound 3.Wherein, the organic solvent is selected from ethanol, acetic acid One kind in ethyl ester, tetrahydrofuran.
The preparation method of compound 4:As R in compound 24For cyano group, in anhydrous methylene chloride, Boron tribromide is present Under, the reaction of -35 DEG C-ambient temperature overnight, after reaction terminates, reaction system is poured into saturated sodium bicarbonate aqueous solution, filtered, is received Collect solid, column chromatography for separation obtains compound 4 respectively.
Compound I preparation method:Compound 4 in methyl alcohol, in the presence of alkali compounds, and hydroxylamine hydrochloride return stirring Reaction, after reaction terminates, reaction system is concentrated in vacuo, and concentrate adds ethyl acetate and water extraction, and washing, organic phase is through post layer Analysis separation, obtains compound I.Wherein, the alkali compounds is selected from potassium carbonate, cesium carbonate, triethylamine, DIPEA In one kind；
Or by compound 3, in anhydrous methylene chloride, in the presence of Boron tribromide, -35 DEG C-room temperature reaction, reaction terminates Afterwards, reaction system is poured into saturated sodium bicarbonate aqueous solution, is filtered, and is collected solid, through column chromatography for separation, is obtained compound I.
Advantage of the present invention：2- phenyl -4- the styryl pyridine compounds that the present invention synthesizes are respectively provided with stronger LSD1 Inhibitory activity and anti tumor activity in vitro.The LSD1 inhibitory activity of compound is better than positive control medicine tranylcypromine, multiple The LSD1 of compound suppresses IC50Less than 1 μM, anti tumor activity in vitro is better than positive control 5 FU 5 fluorouracil.The chemical combination of the present invention Thing represents a kind of LSD1 micromolecular inhibitors with brand new, and the research and development for LSD1 inhibitor class medicines provide base Plinth, effective tool is provided for LSD1 biological function research.Can be as the candidate or lead compound further developed For developing the disease therapeuticing medicine such as antitumor, antiviral, anti-AIDS, and synthetic method is simple, and high income, total recovery reaches More than 40%, be advantageous to popularization and application.
Embodiment
Embodiment is named to elaborate to technical solution of the present invention.
The different cigarette aldehyde (1a) of the 2- of embodiment 1 (2- methoxyphenyls)
The addition 2- bromopyridine -4- formaldehyde (376mg, 2.021mmol) in 50 milliliters of two mouthfuls of flasks, toluene (7mL), K2CO3The aqueous solution (2.76g potassium carbonate is dissolved in 10mL water, 2mL), tetrakis triphenylphosphine palladium (45.2mg, 0.04mmol), nitrogen are protected Reaction 15 minutes is stirred at room temperature under shield, the absolute ethyl alcohol for then adding 2- methoxyphenylboronic acids (407.6mg, 2.682mmol) is molten Liquid (3mL), 3 hours of 92 DEG C of heating responses, reaction system is poured into water, ethyl acetate extraction, combined ethyl acetate layer, according to It is secondary to use water, saturated common salt water washing, anhydrous sodium sulfate drying, filter, after filtrate decompression concentration, concentrate column chromatographic isolation and purification (petroleum ether：Ethyl acetate=6:1) white solid 406.2mg, yield 73.6%, Mp are obtained:51-52℃.1H NMR (400MHz, CDCl3) δ 10.12 (s, 1H), 8.93 (d, 1H, J=4.8Hz), 8.27 (s, 1H), 7.84 (dd, 1H, J1=2.0Hz, J2= 8.0Hz),7.61(dd,1H,J1=1.2Hz, J2=4.8Hz), 7.44 (td, 1H, J1=1.6Hz, J2=8.8Hz), 7.11 (t, 1H, J=7.2Hz), 7.04 (d, 1H, J=8.4Hz), 3.90 (s, 3H)13C NMR(101MHz,CDCl3)δ192.15, 157.86,157.07,150.62,141.48,131.16, 130.75,127.80,124.57,121.18,119.51, 111.41,55.64.HRMS(ESI)calcd for C13H12NO2[M+H]+:214.0868,Found:214.0866.
The 2- of embodiment 2 (the fluoro- 2- methoxyphenyls of 5-) different cigarette aldehyde (1b)
According to the method for embodiment 1,2- methoxies are replaced with the fluoro- 2- methoxyphenylboronic acids (455.8mg, 2.682mmol) of 5- Base phenyl boric acid, obtain yellowish-white solid 389.8mg, yield 83.4%, Mp:72-73℃.1H NMR(400MHz,CDCl3)δ 10.13 (s, 1H), 8.93 (d, 1H, J=4.8Hz), 8.34 (s, 1H), 7.63-7.68 (m, 2H), 7.13 (ddd, 1H, J1= 3.2Hz,J2=7.6Hz, J3=8.8Hz), 6.97 (dd, 1H, J1=4.4Hz, J2=9.2Hz), 3.89 (s, 3H)13C NMR (101MHz,CDCl3)δ191.90, 158.53,156.50,156.48,156.16,153.40,153.38,150.70, 141.65,124.32,120.08, 117.72,117.47,116.86,116.63,112.67,112.59,56.25.HRMS (ESI)calcd for C13H11FNO2[M+H]+:232.0768,Found:232.0770.
Embodiment 3 (E) -2- (2- methoxyphenyls) -4- (4- nitrostyrolenes base) pyridine (2a)
Compound 1a (319.8mg, 1.50mmol) and 4- nitrobenzylphosphonic acid diethylesters are added in 25 milliliters of two-mouth bottles (430.3mg, 1.575mmol), is dissolved with dry DMF (6mL), be slowly added under ice bath potassium tert-butoxide (336.6mg, 3.0mmol), finish, reaction 4 hours is stirred at room temperature, reaction system is slowly poured into frozen water, separate out solid, filter, collect solid Body, white solid 352mg, yield 70.7%, Mp are obtained with re-crystallizing in ethyl acetate:116-117℃.1H NMR(400MHz, CDCl3) δ 8.71 (d, 1H, J=5.2 Hz), 8.25 (d, 2H, J=8.4Hz), 7.90 (s, 1H), 7.78 (d, 1H, J= 6.4Hz), 7.69 (d, 2H, J=8.4Hz), 7.33-7.41 (m, 3H), 7.24 (d, 1H, J=16.4Hz), 7.10 (t, 1H, J =7.2Hz), 7.04 (d, 1H, J=8.0Hz), 3.90 (s, 3H)13C NMR(101MHz,CDCl3)δ157.05,156.93, 149.96,147.40,143.13,142.76,131.23,131.17,130.26,130.21,128.84,127.49, 124.22,122.99,121.13,118.83,111.45,55.76.HRMS(ESI)calcd for C20H17N2O3 [M+H]+: 333.1234,Found:333.1233.
Embodiment 4 (E) -2- (the fluoro- 2- methoxyphenyls of 5-) -4- (4- nitrostyrolenes base) pyridine (2b)
According to the method for embodiment 3,1a is replaced with compound 1b (347mg, 1.5mmol), obtains white solid 332mg, is produced Rate 63.1%, Mp:140-141℃.1H NMR(400MHz,DMSO-d6) δ 8.71 (d, 1H, J=5.2Hz), 8.26 (d, 2H, J =8.8Hz), 7.96 (s, 1H), 7.70 (d, 2H, J=8.8Hz), 7.58 (dd, 1H, J1=3.2Hz, J2=9.6Hz), 7.34- 7.38 (m, 2H), 7.24 (d, 1H, J=16.4Hz), 7.08 (td, 1H, J1=3.2Hz, J2=8.8Hz), 6.97 (dd, 1H, J1 =4.4Hz, J2=9.2Hz), 3.88 (s, 3H)13C NMR(101MHz,CDCl3)δ158.54,156.17,155.70, 155.69,153.23,153.21, 150.01,147.46,143.37,142.65,131.02,130.49,130.04, 129.96,127.52,124.23, 122.89,119.27,117.79,117.55,116.27,116.04,112.78, 112.70,56.42.HRMS(ESI) calcd for C20H15FN2NaO3[M+Na]+:373.0959,Found:373.0959.
Embodiment 5 (E) -3- (2- (2- (2- methoxyphenyls) pyridin-4-yl) vinyl) benzonitrile (2c)
According to the method for embodiment 3,4- nitros are replaced with 3- cyanobenzyls diethyl phosphonate (399mg, 1.575mmol) Benzylphosphonic acid diethylester, obtain white solid 426mg, yield 88.3%, Mp:90-91℃.1H NMR(400MHz,CDCl3)δ8.71 (d, 1H, J=5.2Hz), 7.87 (s, 1H), 7.82 (s, 1H), 7.77 (d, 1H, J=1.6Hz), 7.75 (d, 1H, J= 1.6Hz), 7.60 (d, 1H, J=8.0Hz), 7.49 (t, 1H, J=8.0Hz), 7.42 (td, 1H, 1H, J1=1.6Hz, J2= 9.2Hz),7.32(dd,1H,J1=1.6Hz, J2=5.2 Hz), 7.28 (d, 1H, J=16.0Hz), 7.07-7.15 (m, 2H), 7.04 (d, 1H, J=8.4Hz), 3.89 (s, 3H)13C NMR(101MHz,CDCl3)δ156.93,156.90,149.81, 143.42,137.66,131.62, 131.18,131.02,130.33,130.29,130.18,129.68,129.34, 128.81,122.90,121.10, 118.78,118.56,113.17,111.44,55.74.HRMS(ESI)calcd for C21H17N2O[M+H]+:313.1335,Found:313.1337.
Embodiment 6 (E) -3- (2- (2- (2- methoxyphenyls) pyridin-4-yl) vinyl) benzonitrile (2d)
According to the method for embodiment 3,4- nitros are replaced with 4- cyanobenzyls diethyl phosphonate (399mg, 1.575mmol) Benzylphosphonic acid diethylester, obtain white solid 286mg, yield 59.2%, Mp:120-121℃.1H NMR(400MHz,CDCl3)δ 8.70 (d, 1H, J=5.2Hz), 7.88 (s, 1H), 7.77 (dd, 1H, J1=2.0Hz, J2=7.6Hz), 7.70 (d, 2H, J= 8.4Hz), 7.64 (d, 2H, J=8.4Hz), 7.42 (ddd, 1H, J1=2.0Hz, J2=7.6Hz, J3=8.4Hz), 7.27- 7.33 (m, 2H), 7.20 (d, 1H, J=16.4Hz), 7.10 (td, 1H, J1=0.8Hz, J2=7.2Hz), 7.03 (d, 1H, J= 8.4Hz),3.89(s,3H).13C NMR(101MHz,CDCl3)δ157.00,156.93,149.92,143.26,140.81, 132.61,131.17, 130.72,130.39,130.18,128.89,127.40,122.92,121.12,118.80, 111.44,55.75. HRMS(ESI)calcd for C21H17N2O[M+H]+:313.1335,Found:313.1338.
Embodiment 7 (E) -3- (2- (2- (the fluoro- 2- methoxyphenyls of 5-) pyridin-4-yl) vinyl) benzonitrile (2e)
According to the method for embodiment 3,1a is replaced with compound 1b (347mg, 1.5mmol), with 3- cyanobenzyls phosphonic acids two Ethyl ester (399mg, 1.575mmol) replaces 4- nitrobenzylphosphonic acid diethylesters, obtains white solid 398mg, yield 80.3%, Mp: 185-186℃。1H NMR(400MHz,CDCl3) δ 8.69 (d, 1H, J=5.2Hz), 7.93 (s, 1H), 7.83 (s, 1H), 7.77 (d, 1H, J=8.0Hz), 7.55-7.61 (m, 2H), 7.50 (t, 1H, J=8.0Hz), 7.34 (dd, 1H, J1=1.6Hz, J2= 5.2Hz), 7.30 (d, 1H, J=16.0 Hz), 7.15 (d, 1H, J=16.0Hz), 7.10 (ddd, 1H, J1=3.2Hz, J2= 8.0Hz,J3=9.2Hz), 6.98 (dd, 1H, J1=4.4Hz, J2=8.8Hz), 3.87 (s, 3H)13C NMR(101MHz, CDCl3) δ158.53,156.16,155.59,153.22,153.20,149.96,143.56,137.58,131.69, 131.04, 130.44,130.34,130.09,130.02,129.70,129.18,122.77,119.18,118.55, 117.78, 117.54,116.21,115.98,113.18,112.73,112.65,56.40.HRMS(ESI)calcd for C21H16FN2O[M+H]+:331.1241,Found:331.1241.
Embodiment 8 (E) -4- (2- (2- (2- methoxyphenyls) pyridin-4-yl) vinyl) aniline (3a)
In 25 milliliters of round-bottomed flasks, compound 2a (249mg, 0.75mmol) and anhydrous stannous chloride are added (713.1mg, 3.75mmol), dissolved with absolute ethyl alcohol 10mL, 2 hours of 100 DEG C of back flow reactions.After reaction terminates, it will react System is concentrated in vacuo, and concentrate adds ethyl acetate ultrasonic disperse, adds saturated sodium bicarbonate aqueous solution to stir 30 minutes, is filtered, will Filtrate point takes ethyl acetate layer, successively with water, saturated common salt water washing, anhydrous sodium sulfate drying, filters, filter vacuum concentration, Concentrate column chromatographic isolation and purification (petroleum ether：Acetone=5:1) yellow solid 155.6mg, yield 68.6%, Mp, are obtained:142- 143℃。1H NMR(400MHz,CDCl3) δ 8.61 (d, 1H, J=5.2Hz), 7.78 (s, 1H), 7.72 (d, 1H, J= 7.2Hz), 7.35-7.40 (m, 3H), 7.26 (d, 1H, J=5.6Hz), 7.23 (d, J=16.4Hz, 1H), 7.08 (t, 1H, J =7.2Hz), 7.01 (d, 1H, J=8.4Hz), 6.87 (d, 1H, J=16.4Hz), 6.67 (d, 2H, J=8.4Hz), 3.87 (s,3H).13C NMR(101MHz, CDCl3)δ156.93,156.56,149.52,147.13,145.16,132.90, 131.16,129.85,129.40, 128.45,126.88,122.69,122.30,121.00,118.45,115.13, 111.41,55.75.HRMS(ESI) calcd for C20H19N2O[M+H]+:303.1492,Found:303.1497.
Embodiment 9 (E) -4- (2- (2- (the fluoro- 2- methoxyphenyls of 5-) pyridin-4-yl) vinyl) aniline (3b)
According to the method for embodiment 8,2a is replaced with compound 2b (263mg, 0.75mmol), obtains yellow solid 145mg, Yield 60.3%, Mp:152-153℃.1H NMR(400MHz,DMSO-d6) δ 8.54 (d, 1H, J=5.2Hz), 7.90 (s, 1H),7.54(dd,1H,J1=3.2Hz, J2=10.0Hz), 7.45 (dd, 1H, J1=1.2Hz, J2=5.2Hz), 7.36 (m, 3H),7.25(ddd,1H,J1=3.2Hz, J2=8.0Hz, J3=9.2Hz), 7.18 (dd, 1H, J1=4.8Hz, J2= 9.2Hz), 6.93 (d, 1H, J=16.0Hz), 6.58 (d, 2H, J=8.8Hz), 5.51 (s, 2H), 3.86 (s, 3H)13C NMR (101MHz,DMSO-d6)δ158.00, 155.65,154.73,154.71,153.70,153.68,150.29,149.92, 145.87,134.27,130.42, 130.35,129.06,124.11,122.02,120.55,118.96,117.23, 116.99,116.46,116.23, 114.24,114.03,113.95,56.76.HRMS(ESI)calcd for C20H17FN2NaO[M+Na]+:343.1223,Found:343.1225.
Embodiment 10 (E) -3- (2- (2- (2- hydroxy phenyls) pyridin-4-yl) vinyl) benzonitrile (4a)
Compound 2c (469mg, 1.5mmol) is added in 25 milliliters of round-bottomed flasks, it is molten with anhydrous methylene chloride (5mL) Solution, nitrogen protection, under -35 DEG C of stirrings, the dichloromethane solution (1.13g, 4.5mmol, 5mL) of Boron tribromide is slowly added into, is added Finish, reaction system is slowly increased to room temperature, is stirred overnight at room temperature.Reaction system is added in saturated sodium bicarbonate aqueous solution, Yellow solid is separated out, is filtered, washing, collects yellow solid, column chromatographic isolation and purification (petroleum ether：Acetone=6:1) obtain white solid Body 375mg, yield 83.8%, Mp:178- 179℃.1H NMR(400MHz,CDCl3)δ14.27(s,1H),8.49(d,1H,J =5.2Hz), 7.95 (s, 1H), 7.84-7.87 (m, 2H), 7.80 (d, 1H, J2=8.0Hz), 7.62 (d, 1H, J= 8.0Hz), 7.53 (t, 1H, J=8.0Hz), 7.33-7.36 (m, 2H), 7.31 (d, 1H, J=16.0Hz), 7.15 (d, 1H, J =16.0 Hz), 7.04 (dd, 1H, J1=0.8Hz, J2=8.0Hz), 6.96 (td, 1H, J1=1.2Hz, J2=8.4Hz)13C NMR(101MHz,CDCl3)δ160.15,158.51,146.32,145.37,137.23,132.01, 131.72,131.49, 131.12,130.46,129.80,128.59,126.07,118.85,118.74,118.72, 118.45,116.84, 113.31.HRMS(ESI)calcd for C20H15N2O[M+H]+:299.1179, Found:299.1180.
Embodiment 11 (E) -4- (2- (2- (2- hydroxy phenyls) pyridin-4-yl) vinyl) benzonitrile (4b)
According to the method for embodiment 10,2c is replaced with compound 2d (469mg, 1.5mmol), obtains white solid 300mg, Yield 67.1%, Mp:189-190℃.1H NMR(400MHz,CDCl3) δ 8.63 (d, 1H, J=5.2Hz), 8.43 (s, 1H), 8.13 (d, 1H, J=7.2Hz), 7.93 (d, 2H, J=8.4Hz), 7.83-7.88 (m, 3H), 7.65 (d, 1H, J=4.8Hz), 7.58 (d, 1H, J=16.4Hz), 7.35 (t, 1H, J=6.8Hz), 6.93-6.99 (m, 2H)13C NMR(101MHz,DMSO- d6)δ159.79,157.89,147.15,146.39, 141.26,133.31,133.04,131.98,129.95,128.28, 127.44,120.11,119.28,119.25, 118.44,117.57,111.21.HRMS(ESI)calcd for C20H14N2NaO[M+Na]+:321.0998, Found:321.0999.
Embodiment 12 (E) -3- (2- (2- (5- fluoro-2-hydroxyphenyls) pyridin-4-yl) vinyl) benzonitrile (4c)
According to the method for embodiment 10,2c is replaced with compound 2e (496mg, 1.5mmol), obtains yellow solid 229mg, is produced Rate 48.3%, Mp:184-185℃.1H NMR(400MHz,DMSO-d6) δ 13.99 (s, 1H), 8.64 (d, 1H, J=5.2Hz), 8.45 (s, 1H), 8.17 (s, 1H), 7.97-8.03 (m, 2H), 7.86 (d, 1H, J=16.8Hz), 7.84 (d, 1H, J= 7.6Hz), 7.68 (t, 1H, J=8.0Hz), 7.61 (d, 1H, J=5.2Hz), 7.52 (d, 1H, J=16.8Hz), 7.22 (td, 1H,J1=3.2Hz, J2=8.8Hz), 6.95 (dd, 1H, J1=4.8Hz, J2=8.8Hz)13C NMR(101MHz,DMSO- d6)δ156.84,156.68, 156.65,155.99,154.52,147.37,146.70,137.90,132.82,132.50, 132.24,130.86, 130.67,128.62,120.84,119.78,119.71,119.58,119.50,119.07, 118.82,118.59, 117.56,113.29,113.05,112.57.HRMS(ESI)calcd for C20H13FN2NaO[M+ Na]+:339.0900,Found:339.0903.
Embodiment 13 (E) -2- (4- (3- aminostyryls) pyridine -2- bases) phenol (I-1)
Added in 25 milliliters of round-bottomed flasks and dissolve compound 3a (02mg, 1mmol) anhydrous methylene chlorides (5mL), Nitrogen is protected, and under -35 DEG C of stirrings, is slowly added into the dichloromethane solution (0.75g, 3.0mmol, 5mL) of Boron tribromide, is finished, Reaction system is slowly warmed to room temperature, be stirred overnight at room temperature reaction.Reaction system is slowly added into saturated sodium bicarbonate aqueous solution In, yellow solid is separated out, is filtered, collects solid, column chromatographic isolation and purification (petroleum ether：Acetone=4:1) yellow solid is obtained 134mg, yield 46.4%, Mp:151-152℃.1H NMR(400MHz,DMSO-d6) δ 14.52 (s, 1H), 8.49 (d, 1H, J= 7.2Hz),8.27(s,1H), 8.13(dd,1H,J1=1.2Hz, J2=8.0Hz), 7.60 (d, 1H, J=16.4Hz), 7.52 (dd,1H,J1=1.2Hz, J2=5.6Hz), 7.39 (d, 2H, J=8.8Hz), 7.31 (m, 1H), 6.98 (d, 1H, J=16.4 ), Hz 6.96-6.90 (m, 2H), 6.61 (d, 2H, J=8.4Hz), 5.59 (s, 2H)13C NMR(101 MHz,DMSO-d6)δ 159.97,157.56,150.61,148.26,146.50,135.77,131.72,129.24, 127.30,123.97, 120.00,119.29,119.11,119.05,118.38,116.23,114.27.HRMS(ESI) calcd for C19H17N2O [M+H]+:289.1341,Found:289.1338.
Embodiment 14 (E) -2- (4- (4- aminostyryls) pyridine -2- bases) -4- fluorophenols (I-2)
According to the method for embodiment 13, compound 3a is replaced with compound 3b (320mg, 1mmol), obtains yellow solid 126mg, yield 41.2%, Mp:180-181℃.1H NMR(400MHz,DMSO-d6)δ 14.34(s,1H),8.50(d,1H,J =5.6Hz), 8.32 (s, 1H), 8.03 (dd, 1H, J1=3.2Hz, J2=10.8Hz), 7.65 (d, 1H, J=16.4Hz), 7.52(dd,1H,J1=0.8Hz, J2=5.2Hz), 7.38 (d, 2H, J=8.4Hz), 7.17 (td, 1H, J1=3.2Hz, J2= 8.8Hz), 6.97 (d, 1H, J=16.4Hz), 6.93 (dd, 1H, J1=5.2Hz, J2=9.2Hz), 6.61 (d, 2H, J= 8.4Hz),5.60(s,2H).13C NMR (101MHz,DMSO-d6)δ156.78,156.43,156.41,156.19,154.47, 150.66,148.48, 146.68,136.06,129.24,123.95,119.81,119.77,119.70,119.47, 119.40,118.57, 118.34,116.47,114.28,113.20,112.96.HRMS(ESI)calcd for C19H16FN2O [M+H]+:307.1241,Found:307.1237.
Embodiment 15N'- hydroxyls -3- ((E) -2- (2- (2- hydroxy phenyls) pyridin-4-yl) vinyl) benzamide (I- 3)
In 25 milliliters of round-bottomed flasks, add compound 4a (298mg, 1mmol), hydroxylamine hydrochloride (208.5mg, 3mmol), dissolved with methanol 10mL, lower addition triethylamine (313mg, 3.1mmol) is stirred at room temperature, finishes, back flow reaction is 6 small When.After reaction terminates, system is concentrated in vacuo, concentrate column chromatographic isolation and purification (petroleum ether：Acetone=3:1) white solid is obtained 231mg, yield 69.8%, Mp:185-186℃.1H NMR(400 MHz,DMSO-d6)δ14.32(s,1H),9.70(s,1H), 8.60 (d, 1H, J=5.2Hz), 8.43 (s, 1H), 8.17 (d, 1H, J=6.8Hz), 8.04 (s, 1H), 7.83 (d, 1H, J= 16.8Hz), 7.69 (t, 2H, J=8.0 Hz), 7.64 (d, 1H, J=4.4Hz), 7.48 (t, 1H, J=7.6Hz), 7.41 (d, 1H, J=16.8Hz), 7.35 (td, 1H, J1=1.2Hz, J2=8.4Hz), 6.93-6.98 (m, 2H), 5.92 (s, 2H)13C NMR(101 MHz,DMSO-d6)δ159.86,157.83,151.11,147.07,146.96,136.44,134.68,134.51, 131.90,129.20,128.19,127.46,126.61,126.40,124.62,119.84,119.28,119.23, 118.42,117.20.HRMS(ESI)calcd for C20H18N3O2[M+H]+:332.1394, Found:332.1390.
Embodiment 16N'- hydroxyls -4- ((E) -2- (2- (2- hydroxy phenyls) pyridin-4-yl) vinyl) benzamide (I- 4)
According to the method for embodiment 15,4a is replaced with compound 4b (298mg, 1mmol), obtains white solid 217mg, is produced Rate 65.6%, Mp:205-206℃.1H NMR(400MHz,DMSO-d6)δ14.32(s, 1H),9.75(s,1H),8.59(d, 1H, J=5.2Hz), 8.41 (s, 1H), 8.16 (dd, 1H, J1=1.2Hz, J2=8.0Hz), 7.82 (d, 1H, J=16.8Hz), 7.78 (d, 2H, J=8.8Hz), 7.71 (d, 2H, J=8.8 Hz), 7.64 (d, 1H, J=7.6Hz), 7.44 (d, 1H, J= 16.8Hz),7.35(td,1H,J1=1.2Hz, J2=8.4Hz), 6.93-6.98 (m, 2H), 5.88 (s, 2H)13C NMR (101MHz,DMSO-d6)δ159.85, 157.81,150.87,147.08,146.95,137.03,134.28,134.02, 131.90,127.41,126.64, 126.26,119.81,119.27,119.23,118.42,117.20.HRMS(ESI) calcd for C20H17N3NaO2[M+Na]+:354.1213,Found:354.1211.
Embodiment 17N'- hydroxyls -3- ((E) -2- (2- (5- fluoro-2-hydroxyphenyls) pyridin-4-yl) vinyl) benzoyl Amine (I-5)
According to the method for embodiment 15,4a is replaced with compound 4c (316mg, 1mmol), obtains white solid 120mg, is produced Rate 34.4%, Mp:220-221℃.1H NMR(400MHz,DMSO-d6)δ14.13(s, 1H),9.70(s,1H),8.62(d, 1H, J=4.8Hz), 8.48 (s, 1H), 8.02-8.08 (m, 2H), 7.89 (d, 1H, J=16.4Hz), 7.64-7.70 (m, 3H), 7.48 (t, 1H, J=7.6Hz), 7.41 (d, 1H, J=16.4 Hz), 7.21 (t, 1H, J=7.2Hz), 6.96 (dd, 1H, J1=4.8Hz, J2=8.4Hz), 5.92 (s, 2H)13C NMR(101MHz,DMSO-d6)δ156.84,156.69,156.66, 156.08,154.53,151.08, 147.26,147.17,136.41,134.95,134.53,129.22,128.17, 126.43,124.62,120.66, 119.76,119.68,119.55,119.47,118.77,118.54,117.40, 113.35,113.10.HRMS(ESI) calcd for C20H17FN3O2[M+H]+:350.1299,Found:350.1306.
The LSD1 inhibitory activity evaluation of 2- phenyl -4- styrylpyridinium compounds synthesized by the present invention of embodiment 18 (1) enzyme level LSD1 inhibitory activity is evaluated：
1st, experimental method
Sample is the above-claimed cpd synthesized by embodiment, purifying obtains；Stock sample solution：3-5mg samples are weighed to be placed in In 1.5mL EP pipes, be then configured to the solution that concentration is 20mM with DMSO, 4 DEG C preserve and place, during experiment needed for concentration Diluted with DMSO.By testing sample and LSD1 albumen after incubation at room temperature, add LSD1 reaction substrates H3K4me2 and be incubated anti- Should, it is eventually adding fluorescent dye Amplex and HRPO HRP incubations at room temperature, the exciting light 530nm on ELIASA, hair Penetrate light 590nm detection fluorescence values:
Result of the test calculates IC using SPSS softwares50Value.
2nd, experimental result
Table 1LSD1 inhibitory activity measurement results
an.t.:Undetermined
Can be seen that the most compound of the present invention from upper table experimental result has preferable LSD1 inhibitory activity, more The IC of individual compound50Less than 1 μM, activity is better than positive control medicine 2-PCPA.Wherein activity is most compound I-3, LSD1 by force Inhibitory activity is more than 100 times of 2-PCPA.The compound of the present invention represents the brand-new LSD1 inhibitor of a class formation, is LSD1 The research and development of inhibitor class medicine are provided the foundation, and effective tool is provided for LSD1 biological function research.
(2) anti tumor activity in vitro determines
1st, experimental method
Sample is the compound synthesized by embodiment；Stock sample solution:3-5mg samples are weighed to be placed in 1.5mL EP pipes, Then it is 128 μm of ol/L solution to be configured to concentration with DMSO, and 4 DEG C preserve and place, and the concentration needed for utilizes culture medium during experiment Dilution.
Take the logarithm the cell in growth period, after digestion counts, cell density is adjusted with culture medium, it is thin with 4000-5000 Born of the same parents/hole is seeded in 96 orifice plates, per the μ L of hole 150, after cultivating 24h, discards culture medium, addition has been diluted different dense with culture medium The medicine (128 μM, 64 μM, 32 μM, 16 μM, 8 μM, 4 μM, 2 μM, 1 μM, 0.5 μM) of degree, each concentration sets 6 multiple holes, separately sets Blank control group and positive controls.After medicine effect 72h, 20 μ LMTT are added per hole, continues after cultivating 4h, sucks liquid, Add 150 μ L DMSO, shaken well, detect absorbance at ELIASA 490nm, calculate inhibiting rate, calculation formula is as follows:
Inhibiting rate (%)=(1- administration groups absorbance/blank group absorbance) × 100%
2nd, experimental result
The anti tumor activity in vitro evaluation result of table 2
aHuman colon cancer cells,bMankind mastopathy cell,cHuman hepatocarcinoma cells
Test result indicates that:Institute's test compound shows preferable antitumor activity, wherein compound I-3 and I-4 The inhibitory activity of three kinds of tumour cells to being tested is superior to positive control 5-Fu, and compound I-3 is to the cancer cells of SW- 620 Inhibitory activity is 5 times of 5-Fu, can be as the candidate or lead compound further developed, applied to preparing cancer therapy drug.

Claims (6)

1.2- phenyl -4- styryl pyridine compounds, it is characterised in that there is structure shown in formula I：
In formula I, R1To be monosubstituted or polysubstituted, substituent choosing：NH2、In any one；R2For H, OH, F, Cl, Any one in Br, I；R3For any one in H, OH, CN, F, Cl, Br, I.
2. 2- phenyl -4- styryl pyridine compounds as claimed in claim 1, it is characterised in that
In formula I, R1To be monosubstituted, substituent refers to：NH2、In any one；R2For appointing in H, OH, F, Cl, Br, I Meaning one；R3For any one in H, OH, F, Cl, Br, I.
3. 2- phenyl -4- styryl pyridine compounds as claimed in claim 1 or 2, it is characterised in that preferred followingization Compound:
。
4. 2- phenyl -4- styryl pyridine compounds as claimed in claim 3, it is characterised in that preferred compound I-3 Or I-4.
5. the 2- phenyl -4- styryl pyridine compounds as described in one of claim 1-4 are in medicine preparation Using, it is characterised in that it is used for the preparation of LSD1 inhibitor class medicines as active component.
6. prepare the method for the 2- phenyl -4- styryl pyridine compounds described in claim 1 or 2, it is characterised in that logical Cross following steps realization：
R4For nitro or cyano group, R1, R2, R3Described in claim 1 or 2；
The preparation method of compound 1:Substitute 2- methoxyphenylboronic acids and 2- bromopyridine -4- formaldehyde in toluene, alkali compounds In the presence of palladium catalyst, return stirring reaction, obtain compound 1, wherein, the alkali compounds be selected from potassium carbonate, sodium carbonate, One kind in cesium carbonate, potassium phosphate, described palladium catalyst are selected from (triphenylphosphine) palladium, palladium, double (dibenzalacetones) One kind in palladium, palladium chloride；
The preparation method of compound 2:Compound 1 and substituted benzyl diethyl phosphonate, in DMF, in the presence of alkali compounds, room Warm stirring reaction, after reaction terminates, reaction system is poured into frozen water, filtered, washing, collect solid, dried, obtain compound 2； Wherein, the one kind of the alkali compounds in potassium tert-butoxide, sodium methoxide, sodium hydride, sodium tert-butoxide；
The preparation method of compound 3:As R in compound 24For nitro, then in organic solvent, SnCl2In the presence of, return stirring Reaction, after reaction terminates, reaction system is concentrated in vacuo, and concentrate adds ethyl acetate, saturated sodium bicarbonate aqueous solution stirring, point Organic phase is taken, is washed, is dried, column chromatography for separation obtains compound 3；Wherein, the organic solvent is selected from ethanol, ethyl acetate, four One kind in hydrogen furans；
The preparation method of compound 4:As R in compound 24For cyano group, in anhydrous methylene chloride, in the presence of Boron tribromide, -35 DEG C-ambient temperature overnight reaction, after reaction terminates, reaction system is poured into saturated sodium bicarbonate aqueous solution, filtered, is collected solid Body, column chromatography for separation obtain compound 4；
Compound I preparation method:In methyl alcohol, in the presence of strongly alkaline compound, and hydroxylamine hydrochloride return stirring is anti-for compound 4 Should, after reaction terminates, reaction system is concentrated in vacuo, and concentrate adds ethyl acetate and water extraction, and washing, organic phase is through column chromatography Separation, obtains compound I；Wherein, the strongly alkaline compound is selected from potassium carbonate, cesium carbonate, triethylamine, DIPEA In one kind；
Or by compound 3, in anhydrous methylene chloride, in the presence of Boron tribromide, -35 DEG C-room temperature reaction, after reaction terminates, Reaction system is poured into saturated sodium bicarbonate aqueous solution, is filtered, and is collected solid, through column chromatography for separation, is obtained compound I.
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